Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase

Sustained and complete inhibition of HER3 and its output to PI3K/Akt are required for the optimal antitumor effect of therapeutic inhibitors of the HER2 oncogene. Here, we show that, after inhibition of the HER2 tyrosine kinase with lapatinib, there is PI3K/Akt and FoxO3a-dependent up-regulation of HER3 mRNA and protein. Up-regulated HER3 was then phosphorylated by residual HER2 activity, thus partially maintaining P-Akt and limiting the antitumor action of lapatinib. Inhibition of HER3 with siRNA or a neutralizing HER3 antibody sensitized HER2+ breast cancer cells and xenografts to lapatinib both in vitro and in vivo. Combined blockade of HER2 and HER3 inhibited pharmacodynamic biomarkers of PI3K/Akt activity more effectively than each inhibitor alone. These results suggest that because of HER3-mediated compensation, current clinical inhibitors of HER2 and PI3K/Akt will not block the PI3K pathway completely. They also suggest that therapeutic inhibitors of HER3 should be used in combination with HER2 inhibitors and PI3K pathway inhibitors in patients with HER2- and PI3K-dependent cancers

Color coherent radiation in multijet events from p(p)over-bar collisions at root s=1.8 TeV

We report on a study of color coherence effects in pp- collisions at a center of mass energy √s = 1.8 TeV. The data were collected with the DØ detector during the 1992-1993 run of the Fermilab Tevatron Collider. We observe the presence of initial-to-final state color interference with the spatial correlations between soft and hard jets in multijet events in the central and in forward pseudorapidity regions. The results are compared to Monte Carlo simulations with different color coherence implementations and to the predictions of script O sign(α3s) QCD calculations. © 1997 Elsevier Science B.V